A genome-wide association study identifies genetic loci associated with specific lobar brain volumes

Sven J Van Der Lee ,Tamara B Harris ,Sudha Seshadri ,W T Longstreth ,Saima Hilal ,Tomáš Paus ,Alexa S Beiser ,Pauline Maillard ,Meike W Vernooij ,Maria J Knol ,Hieab H.h Adams ,Rasika A Mathias ,Lei Yu ,Diana Van Heemst ,Philip L De Jager ,Erik B Van Den Akker ,Philippe Amouyel ,M Arfan Ikram ,Bruce M Psaty ,Vilmundur Gudnason ,David A Bennett ,P Eline Slagboom ,Jeroen Van Der Grond ,Konstantinos Arfanakis ,Claudia L Satizabal ,Joshua C Bis ,Lisa R Yanek ,Stéphanie Debette ,Lenore J Launer ,Tien Yin Wong ,Gennady V Roshchupkin ,Helena Schmidt ,Shuo Li ,Manon Bernard ,Wiro J Niessen ,Albert V Smith ,Stefan Böehringer ,Oscar L López ,Ching‐Yu Cheng ,Ganesh Chauhan ,Christopher Chen ,Bernard Mazoyer ,Reinhold Schmidt ,Derrek P Hibar ,Zdenka Pausová ,Qiongqiong Yang ,Diane M Becker ,Edith Hofer ,Neda Jahanshad ,Janet Cheung ,Paul M Thompson ,Yasaman Saba ,Paul Nyquist ,Marian Beekman ,Fabrice Crivello ,Najaf Amin ,Cornelia M Van Duijn ,Wanting Zhao ,Ken Rice ,Kent D Taylor ,Charles Decarli

doi:10.1038/s42003-019-0537-9

Abstract

Brain lobar volumes are heritable but genetic studies are limited. We performed genome-wide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Two loci, associated with occipital (6q22.32) and temporal lobe volume (12q14.3), were previously reported to associate with intracranial and hippocampal volume, respectively. We identified four loci previously unknown to affect brain volumes: 3q24 for parietal lobe volume, and 1q22, 4p16.3 and 14q23.1 for occipital lobe volume. The associated variants were located in regions enriched for histone modifications (DAAM1 and THBS3), or close to genes causing Mendelian brain-related diseases (ZIC4 and FGFRL1). No genetic overlap between lobar volumes and neurological or psychiatric diseases was observed. Our findings reveal part of the complex genetics underlying brain development and suggest a role for regulatory regions in determining brain volumes.

Highlights

Brain lobar volumes are heritable but genetic studies are limited
Functions of the frontal brain lobe include reasoning, movement, social behavior, planning, parts of speech, and problem solving[1]; functions attributed to the parietal lobe include recognition and perception of stimuli[2]; functions attributed to the temporal lobe include memory and speech[3]; and lastly, visual input is mainly processed by the occipital lobe
Using a family-based approach, we found an age- and sex-adjusted heritability (h2) for occipital lobe of 50% (95% confidence interval (CI) 38–62%), for frontal lobe of 52%, for temporal lobe of 59%, and for parietal lobe of 59% (Supplementary Data 5)

Summary

Introduction

We performed genomewide association studies of frontal, occipital, parietal and temporal lobe volumes in 16,016 individuals, and replicated our findings in 8,789 individuals. We identified six genetic loci associated with specific lobar volumes independent of intracranial volume. Brain diseases with lobe-specific abnormalities include Alzheimer’s disease (in particular early onset), frontotemporal lobar degeneration[4], temporal lobe epilepsy[5], primary progressive aphasia, and cortical basilar ganglionic degeneration. Environmental factors, such as smoking and hypertension, affect lobar brain volumes[6], but previous studies have shown that genetic differences across individuals contribute to variability in volumetric brain measures[7,8]. We shed light on common genetic variants determining human brain volume and allow for a deepened understanding of the genetic architecture of the brain lobes

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Conclusion